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Biomedical subjects

E C Holmes

Publications and source records attributed to E C Holmes.

At least 19 recordsLinked to original sources
PubMed1992

Convergent and divergent sequence evolution in the surface envelope glycoprotein of human immunodeficiency virus type 1 within a single infected patient.

In an investigation of the evolution of the third hypervariable loop of gp120 (V3), the principal neutralization determinant of human immunodeficiency virus type 1, we have analyzed 89 V3 sequences of plasma viral RNA purified from peripheral blood samples donated over 7 years by an infected hemophiliac. Considerable sequence diversity in the V3 region was found at all time points after seroconversion. Phylogenetic analysis revealed that an important diversification had occurred by 3 years postinfection and that, subsequently, most sequences could be allocated to either one of two major lineages that persisted throughout the remainder of the infection. Rapid changes in frequency of the most common sequences and the observation that the same hexapeptide motif (GPGSAV) at the crown of the V3 loop has evolved convergently provide strong evidence that selective processes determine the evolutionary fate of sequence variants in this region.

Amino Acid Sequence↗
PubMed1992

Surgical treatment and chemotherapy for pulmonary metastases from osteosarcoma.

Between 1971 and 1991, 247 patients with stage I osteosarcoma were treated at UCLA. Patients were treated in four sequential groups, with group 1 receiving surgery alone, and groups 2 through 4 receiving various adjuvant chemotherapeutic regimens. The incidence of lung metastases in these patients decreased from 92% (group 1) to 31% (group 4), while the proportion of patients undergoing pulmonary resection increased (17% vs 82%). Overall 5-year survival rate among patients with pulmonary metastases increased from 0 in group 1 to 41% (actuarial) in group 4. No clinical factor correlated significantly with outcome using univariate analysis, although there was a trend toward prolonged survival in those with longer disease-free intervals. Adjuvant chemotherapy and resection of pulmonary metastases have transformed a uniformly fatal condition into one with a reasonable expectation of long-term survival.

Adolescent↗
PubMed1992

Analysis of a new hepatitis C virus type and its phylogenetic relationship to existing variants.

Sequences obtained in the 5' non-coding region (5'NCR) of hepatitis C virus (HCV) were obtained from Scottish blood donors and compared with previously published HCV sequences. Phylogenetic analysis revealed the existence of three distinct groups of sequences; two of these corresponded to the recently described HCV types 1 and 2 variants, while viral sequences detected in around a third of the blood donors formed a separate phylogenetic group that probably represents infection with a novel virus species. Nucleotide sequences of this latter group differed from all previously published 5'NCR sequence variants by at least 9%. This new virus type also differed considerably from previously published variants in other regions of the viral genome (core, NS-3 and NS-5), with corrected nucleotide distances of 15, 43 and 49% respectively from the prototype HCV-1 sequence. Formal phylogenetic analysis of each of the coding regions confirmed that HCV type 1 variants could be clearly differentiated into regional variants (Far East and U.S.A./European), in contrast to the clearly overlapping geographical distributions of the main HCV types in U.K. blood donors. We discuss the evidence for and against the hypothesis that the three main phylogenetic groups identified in this study represent separate species of HCV.

Amino Acid Sequence↗
PubMed1991

Smoking behavior following diagnosis in patients with stage I non-small cell lung cancer.

The cigarette-smoking behavior of 840 patients with resected Stage I non-small cell lung cancer was analyzed prospectively for up to four years following diagnosis. Lung cancer patients were heavier smokers at diagnosis than other cancer patients and the general population. At one year, only 16.8 percent of the 317 current smokers at baseline, who were followed for two years or longer, continued to smoke, while 83.2 percent of patients either quit permanently (53.0 percent) or for some time period (30.2 percent). By two years, permanent cessation stabilized at over 40 percent; however, the prevalence of continuing smoking decreased through all periods of follow-up. Subjects who tried to quit or did quit permanently were more likely to be female and healthier than continuous smokers.

Carcinoma, Non-Small-Cell Lung↗
PubMed1991

Immunopathological features of human pulmonary tumors following low-dose interleukin-2.

We administered preoperative low-dose interleukin-2 (IL-2) to 10 patients undergoing thoracotomy for pulmonary tumors. The in vivo effect of IL-2 on tumor-associated lymphocyte activity was assessed in the resected specimens by immunohistochemistry and compared with observations in 45 patients who did not receive IL-2. H & E evaluation revealed an increase in intra- and peritumoral lymphocyte infiltration in the IL-2-treated patients. Immunopathological evaluation with monoclonal antibodies revealed that this lymphocyte infiltration was predominantly CD5-positive T cells. The amount of intra- and peritumoral lymphocyte activity correlated with the dose of IL-2 administered (6000-90,000 international units/kg every 8 h for 48 h. IL-2-treated patients showed increases in T-cell-associated activation markers (IL-2 alpha-receptor, transferrin receptor and HLA-DR) on peritumoral lymphocytes, but not on intratumoral lymphocytes. We previously reported that low-dose IL-2 increases the intrinsic natural killer cell cytotoxicity of intratumoral lymphocytes and suggest that this lymphocyte infiltration is further evidence that low-dose IL-2 can augment in vivo lymphocyte activity at the tumor site.

Aged↗
PubMed1991

Different rates of substitution may produce different phylogenies of the eutherian mammals.

In an attempt to resolve some points of branching order in the phylogeny of the eutherian mammals, a phylogenetic analysis of 26 nuclear and 6 mitochondrial genes was undertaken using a maximum likelihood method on a constant rate stochastic model of molecular evolution. Seventeen of the nuclear genes gave a primates/artiodactyls grouping highest support whereas three of the mitochondrial genes found a rodents/artiodactyls grouping to be best supported. The primates/rodents grouping was never the best supported. On the assumption that rodents are indeed an outgroup to primates and artiodactyls and that the latter taxa diverged 70 million years ago, an estimation was made, for each gene, of the time of divergence of the rodent lineage. In most cases such estimates were beyond the limits set by present interpretations of the paleontological record as were many estimates of the divergence time of mouse and rat. These results suggest that, although there is locus variation, the divergent position of the rodent lineage may be an artifact of an elevated rate of nucleotide substitution in this order.

Animals↗
PubMed1991

Mediastinal masses: magnetic resonance imaging in comparison with computed tomography.

Seventy-eight patients with mediastinal abnormalities were imaged with magnetic resonance imaging (MRI) to evaluate mediastinal masses and associated lung, pleural, or chest wall disease. Magnetic resonance images were compared with computed tomography (CT) scans, which were available in 45 patients. While MRI and CT were equally effective in demonstrating mediastinal lesions, CT was superior for displaying calcification within a mass in eight patients and for demonstrating associated lung abnormality in four patients. Computed tomography should remain the imaging procedure of choice after chest radiography to evaluate mediastinal masses, although MRI may be indicated in selected patients.

Adolescent↗
PubMed1991

The role of extrapleural pneumonectomy in malignant pleural mesothelioma. A Lung Cancer Study Group trial.

Malignant pleural mesothelioma is usually a fatal cancer for which operation has been the mainstay of treatment because chemotherapy and radiation are relatively ineffective. The choice of operation for malignant pleural mesothelioma remains controversial. Extrapleural pneumonectomy has been advocated because it allows complete removal of gross tumor and can be associated with long-term survival. To evaluate extrapleural pneumonectomy, we conducted a prospective multiinstitutional trial in patients with biopsy-proved previously untreated malignant pleural mesothelioma. Criteria for extrapleural pneumonectomy were (1) potentially completely resectable unilateral disease by computed tomography scan, (2) predicted postresection forced expiratory volume in 1 second greater than 1 L/sec, and (3) no other major medical problems. Patients who were not candidates for extrapleural pneumonectomy had a more limited operation with or without adjuvant therapy or had nonsurgical treatment. From September 1985 to June 1988 83 eligible patients (64 male, 19 female) were entered. The mean age for all patients was 59.7 years. Only 20 of the 83 patients (24%) underwent extrapleural pneumonectomy. Three of these 20 patients (15%) died postoperatively. The recurrence-free survival was significantly longer for the patients undergoing extrapleural pneumonectomy than for the other two groups (p = 0.03), but there was no difference in overall survival among the three groups. In univariate analyses, epithelial versus sarcomatoid and mixed histologic findings and platelet count less than 400,000 were associated with a better overall survival (p = 0.02), and performance status (Karnofsky less than 80) was predictive of recurrence (p = 0.02). In a multivariate analysis, histologic findings, sex, age, extrapleural pneumonectomy, weight loss, and performance status all had no significant impact on survival. Extrapleural pneumonectomy was associated with a greater likelihood of relapse in distant sites than were limited operation and nonsurgical treatment. We conclude that (1) only a small proportion of all patients with malignant pleural mesothelioma are candidates for extrapleural pneumonectomy, (2) extrapleural pneumonectomy carries a significant operative mortality and does not seem to improve overall survival compared with more conservative forms of treatment, (3) extrapleural pneumonectomy alters the patterns of relapse, and (4) factors previously thought to have an impact on survival in other series did not affect outcome in this trial.

Diaphragm↗
PubMed1990

Adjuvant treatment in resected lung cancer.

There have been many attempts to develop effective postoperative adjuvant therapy in patients with resected lung cancer. Metastatic disease is the commonest site of first recurrence. In squamous cell carcinoma local failure is another major problem and in adenocarcinoma brain metastases are frequent. There is evidence to suggest that radiotherapy can prevent local recurrence but does not appear to impact on survival. Response rates to chemotherapy alone and chemo-radiotherapy with prolongation of disease-free survival have been encouraging in locally advanced (resected stage II, III) disease when treated postoperatively. Results of clinical trials using immunotherapy or chemotherapy in early stage disease have been disappointing. Several prospective randomized studies by the Lung Cancer Study Group were undertaken to assess the merits of various adjuvant treatments and are presented.

Combined Modality Therapy↗
PubMed1990

TNF-alpha and IFN-gamma reverse IL-4 inhibition of lymphokine-activated killer cell function.

Recombinant IL-4 inhibits IL-2-induced lymphokine-activated killer (LAK) cell development of PBMC. We evaluated the effect of various cytokines in reversing IL-4-mediated LAK inhibition. PBMC were cultured in IL-2 (10-1000 u/ml) with or without IL-4 (2-100 u/ml) and tested for cytotoxicity against the NK-sensitive K562 cells and NK-resistant UCLA-SO-M14 cells. Addition of IL-4 at the beginning of culture suppresses LAK activity in a dose-dependent fashion. Addition of IFN-gamma or TNF-alpha partially reverses IL-4-mediated inhibition (30-100%) in a dose-dependent fashion. IFN-gamma and TNF-alpha must be added within the first 24 hr of initiating culture in order to reverse IL-4 inhibition. Furthermore, IFN-gamma and TNF-alpha are most effective at reversing IL-4 inhibition at low concentrations of IL-2 (less than 100 u/ml). Addition of other IL-2-induced cytokines such as GM-CSF (50 u/ml), M-CSF (250 u/ml), and IFN-alpha (10-10,000 u/ml) fails to reverse IL-4 inhibition. In addition to suppression of LAK induction, IL-4 also inhibits IL-2-induced IFN-gamma and TNF-alpha protein production in PBMC. The reversal of IL-4-mediated LAK inhibition by TNF-alpha and IFN-gamma may therefore be due to resupply of these endogenously suppressed cytokines.

Colony-Stimulating Factors↗
PubMed1990

Differential regulation by interleukin-4 and interferon-gamma of an autologous melanoma-specific cytotoxic T-cell clone and the tumor-infiltrating lymphocytes from which it was established.

To investigate the specificity of human tumor-infiltrating lymphocytes (TIL) against autologous tumors, TIL from five metastatic melanoma patients were expanded with rIL-2 and assessed for cytotoxicity in chromium release assays. TIL from a patient showing preferential cytotoxicity against autologous melanoma cells were further analysed. TIL were cloned by limiting dilution. Four out of 27 clones showed substantial cytotoxicity against autologous melanoma and one clone, designated as No. 8a-5 (CD3+, CD4-, CD8+, CD56-), selectively killed autologous melanoma but did not kill six different allogeneic melanoma, K562, or autologous or allogeneic Con A lymphoblast targets. Cytotoxicity of No. 8a-5 cells was inhibited by anti-HLA class I MAb (w6/32), by anti-beta 2-microglobulin MAb, and by anti-CD3 (OKT3) MAb, suggesting that the specific cytotoxicity was HLA class I-restricted and that the clone utilized the T-cell receptor complex for recognition of targets. Pretreatment with rIFN-gamma increased the sensitivity of autologous melanoma targets to lysis by No. 8a-5 cells. Exogenous rIL-4 enhanced [3H]TdR incorporation by these TIL. In contrast, rIFN-gamma reduced the sensitivity of the autologous melanoma to lysis by uncloned TIL, and rIL-4 suppressed the cytotoxicity and cell proliferation of uncloned TIL. These results indicate that both specific and non-specific cytotoxic cells can be developed from the same TIL and that these can be differentially regulated.

Antibodies, Monoclonal↗
PubMed1990

Frequent amplification of the bcl-1 locus in poorly differentiated squamous cell carcinoma of the lung. The Lung Cancer Study Group.

The bcl-1 locus on chromosome 11 at band q13 has been shown to be rearranged in some chronic B lymphoid malignancies with the t(11;14)(q13;q32). Chromosome 11 abnormalities occur in solid tumors including squamous cell cancers and adenocarcinomas. We have recently reported the frequency amplification of the bcl-1 locus in squamous cell carcinomas of head and neck origin, and increased copy number also has been found in some breast adenocarcinomas. In this investigation, we analyzed the arrangement, copy number and expression of this locus in 111 primary non-small cell lung cancers. Bcl-1 was found to be amplified three- to 10-fold in seven fresh tumors. Whereas none of 51 adenocarcinomas showed bcl-1 amplification, six of 46 squamous cell carcinomas revealed an increase in bcl-1 copy number. This amplification was more frequently associated with larger and more poorly differentiated tumors. None of the cancers showed rearrangement of this locus.

Adenocarcinoma↗
PubMed1989

Surgical adjuvant therapy of non-small-cell lung cancer.

Results of several studies by the Lung Cancer Study Group have shown that postoperative adjuvant chemotherapy enhances survival following surgery for lung cancer. The 18-month disease-free survival almost doubled in one study using cyclophosphamide, doxorubicin, cisplatin (CAP) chemotherapy postoperatively. The recurrence rate remained significant, however. Patients with more advanced resectable disease seem to benefit most from postoperative chemotherapy. Results also suggest that CAP delays recurrences more effectively in patients with nonsquamous vs. squamous lung carcinoma. There has been considerable interest in the use of preoperative adjuvant therapy as well. Findings from studies of preoperative or induction therapy--either chemotherapy alone or in combination with radiation therapy--have shown high response rates and that patients with unresectable disease can be converted to technically resectable. Although preoperative therapy can cause difficulties with surgical dissection, surgical morbidity is acceptable. Preoperative chemotherapy and radiotherapy followed by surgical resection clearly eliminates local recurrence. Systemic recurrences remain a significant problem. The evidence, as yet, does not indicate that preoperative adjuvant therapy prolongs survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Isolated pulmonary nodules in head and neck cancer patients.

Not infrequently, a patient with newly diagnosed head and neck cancer is noted on preoperative chest radiography to have a solitary pulmonary nodule. It is initially unclear whether the pulmonary nodule is a benign lesion or a metastatic or primary lung malignancy. Considerable controversy exists regarding the evaluation of such patients as well as the treatment, assuming that the pulmonary lesion is malignant. We have reviewed the UCLA experience with patients who had head and neck cancers and pulmonary cancers no more than 5 years apart, and reviewed the literature on early stage lung cancer. We present a rational approach to the workup and treatment of patients with head and neck cancer and a pulmonary nodule on chest radiography.

Adenocarcinoma↗
PubMed1989

Tumour necrosis factor production by IL-2-activated macrophages in vitro and in vivo.

Purified human and murine monocytes can be activated in vitro by human recombinant IL-2 to secrete tumour necrosis factor (TNF). TNF mRNA is detected within 4 h of addition of IL-2. Signal transduction does not appear to require expression of the Tac peptide of the IL-2 receptor. IL-2 does, however, induce Tac mRNA and Tac peptide expression on peripheral blood monocytes (PBM). In addition to these in vitro studies, PBM retrieved from IL-2-treated cancer patients and mice have been shown to have a greatly increased capacity for TNF production. These studies identify a pathway for macrophage activation by IL-2 both in vitro and in vivo. They also suggest a mechanism for some of the immunoregulatory and toxic effects of IL-2 based immunotherapy regimens.

Animals↗
PubMed1988

Interleukin-1 and tumor necrosis factor production by tumor-associated mononuclear leukocytes and peripheral mononuclear leukocytes in cancer patients.

The production of interleukin-1 (IL-1) and tumor necrosis factor (TNF) by tumor-associated mononuclear leukocytes (TAML) and peripheral mononuclear leukocytes (PMBL) from 9 otherwise untreated patients with a variety of malignancies (lung, sarcoma, stomach, renal) was assessed. Cells were cultured for 24 hr in vitro in the presence or absence of lipopolysaccharide (LPS), and IL-1 and TNF levels were measured in culture supernatants. TNF production was comparable between TAMLs and PBMLs. However, a striking defect in IL-1 production by TAMLs was noted. There was no basal production of IL-1 and LPS-stimulated TAMLs produced only 1% the amount of IL-1 produced by LPS-stimulated PBMLs.

Biological Assay↗